A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson's disease

Abstract

Gene transfer of dopamine-synthesizing enzymes into the striatal neurons has led to behavioral recovery in animal models of Parkinson's disease (PD). We evaluated the safety, tolerability, and potential efficacy of adeno-associated virus (AAV) vector-mediated gene delivery of aromatic L-amino acid decarboxylase (AADC) into the putamen of PD patients. Six PD patients were evaluated at baseline and at 6 months, using multiple measures, including the Unified Parkinson's Disease Rating Scale (UPDRS), motor state diaries, and positron emission tomography (PET) with 6-[(18)F]fluoro-L-m-tyrosine (FMT), a tracer for AADC. The short-duration response to levodopa was measured in three patients. The procedure was well tolerated. Six months after surgery, motor functions in the OFF-medication state improved an average of 46% based on the UPDRS scores, without apparent changes in the short-duration response to levodopa. PET revealed a 56% increase in FMT activity, which persisted up to 96 weeks. Our findings provide class IV evidence regarding the safety and efficacy of AADC gene therapy and warrant further evaluation in a randomized, controlled, phase 2 setting.

Figure 1

Changes in UPDRS scores. Absolute changes in scores from baseline to 6 months for individual patients. OFF, off-medication state; ON, on-medication state; UPDRS, Unified Parkinson's Disease Rating Scale.

Figure 2

Evaluation of patients' diaries and daily doses of levodopa equivalents. For each 30-minute interval throughout the day, the patients recorded whether they were mobile (ON), immobile (OFF), or asleep. They also recorded the time with troublesome dyskinesias (Dyskinesia). The graph shows the percentage of hours in a day spent in each condition at baseline and at 6 months. The numbers on the bars indicate the mean daily doses of levodopa equivalents (mg). OFF, off-medication state; ON, on-medication state.

Figure 3

Short-duration response to levodopa. Comparison of short-duration response to levodopa before (blue) and after gene therapy (brown) in three patients (A-4, A-5, and A-6). Patients took 100 mg of levodopa with 25 mg benserazide orally after 20 hours without dopaminergic medication. Values represent means and SE of three trials. Upper panels: plasma levodopa levels; lower panels: Unified Parkinson's Disease Rating Scale motor scores. *P < 0.05.

Figure 4

FMT-PET images. Axial images at the level of the putamen are shown before and 24 weeks after gene therapy for all six patients. Increased FMT uptake persisted until 96 weeks in two patients. The 4-week images are not shown because they are similar to the 24-week images. FMT, 6-[¹⁸F]fluoro--m-tyrosine; PET, positron emission tomography.